This program project focuses on the molecular mechanisms and the genes involved in the pathogenesis and progression of B- and T-cell chronic lymphocytic leukemia. It consists of four related and highly interdependent projects and two core facilities. Project 1 concerns the role of BCL2 and TCL1 in the pathogenesis of B-CLL and T-CLL respectively. We propose to investigate the mechanisms of up-regulation of BCL2 in B-CLL and the mechanisms of action of TCL1 in T-CLL. We propose to investigate the mechanisms of up-regulation of BCL2 in B- CLL and the mechanisms of action of TCL1 in T-CLL. We also propose to identify the role of other genes that are involved in the progression of B- and T-CLL. The second project focuses on the use of the positional cloning approach to clone a gene at 13q14.3 that is involved in deletions in most human B-CLLs. We have already sequenced over 750 Kb of the critical chromosomal region and are testing candidate genes for mutations and deletion in B-CLL The third project focuses on the use of Tcll knock out mice to assess the role of Tcll in lymphoid development. In addition this project proposes to investigate the cooperation of TCL1 deregulation and ATM loss of function in leukemogenesis. The fourth project focuses on the tridimensional characterization of Tcll and Mtcpl and their mutants and on the interaction of these two oncoproteins with other proteins. The two core facilities, administrative, and protein chemistry, provide outstanding core support for the scientific activities described in the proposal.